EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations


BACKGROUND Pontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1. METHODS We selected a cohort of 99 PCH patients (90 families) tested negative for mutations in the TSEN genes, RARS2, VRK1 and CASK. Patients in this cohort were referred with a tentative diagnose PCH type 1, 2, 4, 7 or unclassified PCH. Genetic analysis of the EXOSC3 gene was performed using Sanger sequencing. Clinical data, MR images and autopsy reports of patients positive for EXOSC3 mutations were analyzed. RESULTS EXOSC3 mutations were found in twelve families with PCH subtype 1, and were not found in patients with other PCH subtypes. Identified mutations included a large deletion, nonsense and missense mutations. Examination of clinical data reveals a prolonged disease course in patients with a homozygous p.D132A mutation. MRI shows variable pontine hypoplasia in EXOSC3 mediated PCH, where the pons is largely preserved in patients with a homozygous p.D132A mutation, but attenuated in patients with other mutations. Additionally, bilateral cerebellar cysts were found in patients compound heterozygous for a p.D132A mutation and a nonsense allele. CONCLUSIONS EXOSC3 mediated PCH shows clear genotype-phenotype correlations. A homozygous p.D132A mutation leads to PCH with possible survival into early puberty, and preservation of the pons. Compound heterozygosity for a p.D132A mutation and a nonsense or p.Y109N allele, a homozygous p.G31A mutation or a p.G135E mutation causes a more rapidly progressive course leading to death in infancy and attenuation of the ventral pons.Our findings imply a clear correlation between genetic mutation and clinical outcome in EXOSC3 mediated PCH, including variable involvement of the pons.

DOI: 10.1186/1750-1172-9-23

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@inproceedings{Eggens2014EXOSC3MI, title={EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations}, author={Veerle RC Eggens and Peter Barth and Jikke-Mien F. Niermeijer and Jonathan N. Berg and Niklas Dar{\'i}n and Abhijit Dixit and Joel Fluss and Nicola C. Foulds and Darren J. Fowler and Tibor Hortob{\'a}gyi and Thomas S Jacques and Mary Dolores King and Periklis Makrythanasis and Adrienn M{\'a}t{\'e} and James A. R. Nicoll and Declan M. O’Rourke and Sue M. Price and Andrew N. Williams and Louise C. Wilson and Mohnish Suri and Lāszl{\'o} Sztriha and Marit B Dijns-de Wissel and Mia T van Meegen and Fred van Ruissen and E. Aronica and Dirk Troost and Charles B. L. M. Majoie and Henk A. Marquering and Bwee Tien Poll-Th{\'e} and Frank Baas}, booktitle={Orphanet journal of rare diseases}, year={2014} }